tbuckley/cabot-search huggingface dataset:
SOGUG-vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.
Authors: Guillermo de Velasco, Carlos Alvarez-Fernandez, Francisco Jose Alvarez Marquez, Oscar Reig Torras, Juan Antonio Virizuela, Urbano Anido, Aitor Azkarate, Pablo Gajate, Iciar Garcia Carbonero, Aina Iranzo Sabater, Rebeca Lozano, Eduardo Pujol
Journal: Journal of Clinical Oncology (2023)

TPS4606 Background: The current standard of care in non-progressors to first-line platinum-based chemotherapy for unresectable locally advanced or metastatic urothelial carcinoma (UC) is maintenance treatment with avelumab plus best supportive care (BSC). The Checkmate 032 trial showed that the highest ORR (42.4%) was achieved by the combination of Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg in refractory mUC (1), with a manageable safety profile and better outcomes compared to other treatment arms. The trial aims to consolidate the clinical benefit achieved from first-line chemotherapy with the combination of nivolumab 1mg/kg plus ipilimumab 3mg/kg followed by nivolumab. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of Ipilimumab and nivolumab followed by nivolumab maintenance therapy in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line chemotherapy. Main eligibility criteria include: Male or female subjects ≥ 18 yrs old with written informed consent, ECOG performance status 0 or 1, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium (UCC), patient inclusion within 3-12 weeks after the last chemo dose, no progressive disease per RECIST v1.1, available tumor tissue at baseline, adequate normal organ and marrow function (Haemoglobin ≥ 9.0 g/dL, ANC &gt; 1500 per mm3, platelets ≥ 100,000 per mm3, bilirubin ≤ 1.5 X ULN, transaminases ≤ 2.5X ULN, creatinine clearance &gt; 30 mL/min). The primary endpoint is Progression Free Survival (PFS). Secondary objectives include: objective response rate (ORR), duration of response (DoR), overall survival (OS), chemotherapy overall survival (cOS), and chemotherapy progression-free survival (cPFS). Additionally, the study also has safety secondary objectives. Dynamic biomarker analysis will be performed. As of January 2023, 5 out of the planned 66 patients have been enrolled in the study. 1) Sharma P et al. J Clin Oncol. 2019. Clinical trial information: EudraCT 2021-005364-22 .
CLDN6 CAR-T cell therapy of relapsed/refractory solid tumors ± a CLDN6-encoding mRNA vaccine: Dose escalation data from the BNT211-01 phase 1 trial using an automated product.
Authors: Andreas Mackensen, John B. A. G. Haanen, Christian Koenecke, Winfried Alsdorf, Eva Maria Wagner-Drouet, Daniel Heudobler, Peter Borchmann, Carsten Bokemeyer, Sebastian Klobuch, Nadine Kutsch, Fabian Müller, Alexander Desuki, Florian Lüke, Erol Wiegert, Carina Flemmig, Catrine Schulz-Eying, Benjamin Rengstl, Liane Preußner, Özlem Türeci, Uğur Şahin
Journal: Journal of Clinical Oncology (2023)

2518 Background: We are developing a chimeric antigen receptor (CAR)-T cell therapy targeting claudin 6 (CLDN6), an oncofetal antigen that is undetectable in healthy somatic tissue and highly expressed in various solid cancers. Autologous CLDN6 CAR-T cells are being tested alone and in combination with CLDN6-encoding CAR-T cell Amplifying RNA Vaccine (CARVac), a nanoparticulate RNA vaccine designed to stimulate and expand CLDN6 CAR-T cells. Methods: The ongoing first-in-human trial BNT211-01 evaluates the safety and feasibility of CLDN6 CAR-T cell transfer ± CARVac in lymphodepleted patients with relapsed/refractory solid tumors. Patients are pre-screened for CLDN6 expression with a cut-off of 50% positivity of intermediate or strong intensity by immunohistochemistry staining. Key endpoints are safety, tolerability, and anti-tumor activity. Pharmacokinetics of adoptively transferred CAR-T cells in peripheral blood is monitored by quantitative PCR. Dose escalation proceeds according to a classical 3+3 design, testing CLDN6 CAR-T cells at each dose level as both as monotherapy and in combination with CARVac. We previously reported results from 22 patients from 4 dose escalation cohorts with a manual CAR-T production process ± CARVac (ESMO-IO LBA38) which followed the same methodology. We observed durable responses along with a manageable safety profile, in line with commercial CAR-T products used to treat B-cell malignancies. No on-target/off-tumor toxicity and only a single case of (grade 1) neurotoxicity was observed. Given the encouraging efficacy, we have implemented an automated process to scale-up manufacturing. Accordingly, we are repeating the dose escalation with an automated CAR-T cell product, and with a modified CARVac regimen. As of 1 st February 2023, 7 patients with epithelial ovarian carcinoma (EOC), 4 with testicular germ cell tumors (GCT), and a further 5 patients with tumors of various indications have been infused with CAR-T cells up to DL2. We intend to submit efficacy, safety and CAR T-cell pharmacokinetics data from 5 cohorts treated with 1x10 6 , 1x10 7 or 1x10 8 CLDN6 CAR-T cells ± CARVac with a data cut-off of March 14 th , 2023 from ≥17 treated patients as a late-breaking abstract. Clinical trial information: NCT04503278 .
Subgroup analyses of safety and efficacy by number and types of prior lines of treatment in FRESCO-2, a global phase III study of fruquintinib in patients with refractory metastatic colorectal cancer.
Authors: Arvind Dasari, Sara Lonardi, Rocio Garcia-Carbonero, Elena Elez, Takayuki Yoshino, Alberto F. Sobrero, James C. Yao, Pilar Garcia-Alfonso, Judit Kocsis, Antonio Cubillo, Andrea Sartore-Bianchi, Taroh Satoh, Violaine Randrian, Jiri Tomasek, Geoff Chong, Zhao Yang, Rajash Pallai, Iris Carton, Josep Tabernero, Cathy Eng
Journal: Journal of Clinical Oncology (2023)

3604 Background: Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC). Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, was evaluated in the global phase III FRESCO-2 study (NCT04322539) and demonstrated a clinically meaningful and statistically significant improvement in OS and PFS with a favorable safety profile. Here we report subgroup analyses of efficacy and safety by prior lines (PL) and types of anti-cancer treatment (Tx) for metastatic disease (MD). Methods: FRESCO-2 was conducted in the US, Europe, Japan &amp; Australia, comparing F + best supportive care (BSC) with Placebo (P) + BSC. Pts were given 5 mg PO, QD, 3 wks on, 1 wk off, in a 28-day cycle. Eligible pts received prior chemotherapy, anti-VEGF, and if RAS wild type, anti-EGFR therapies; if BRAFV600E mutant or MSI-H, and appropriate targeted regimen; and had progressed on, or were intolerant to, trifluridine/tipiracil (TAS-102) and/or regorafenib (R). Subgroup (sbgrps) analyses for efficacy and safety were performed according to number of prior lines of tx (LOT) and by types of therapy. Results: A total of 691 pts were randomized; F:461 vs P:230. The median number of prior lines of anti-cancer tx for metastatic disease F vs P was 4 (2, 16) vs 4 (2, 12). F improved OS and PFS compared to P for all sbgrps and prior tx for MD, consistent with those of the ITT population (pop). (Table: OS reported by sbgrps and prior tx for MD). Occurrence of adverse events (AEs) and serious adverse events were generally balanced between F vs P and consistent across all subgroups. The most common ≥ G3 AEs in ≥5% of pts on F within majority of sbgrps were hypertension, asthenia and palmar plantar erythrodysesthesia and were consistent with the overall safety population. Additional analyses based on duration of prior anti-VEGF and last therapy prior to F will be presented at the conference. Conclusions: F demonstrated clinically meaningful improvement in OS, PFS with an acceptable safety profile across all sbgrps. These results were consistent with the effect observed in the overall population; irrespective of previous tx with anti-VEGF, anti-EGFR, TAS-102 and R further supporting F as a potential new tx option for pts with refractory mCRC. Clinical trial information: NCT04322539 . [Table: see text]
Phase 2 trial of pembrolizumab and olaparib (POLAR) maintenance for patients (pts) with metastatic pancreatic cancer (mPDAC): Two cohorts B non-core homologous recombination deficiency (HRD) and C exceptional response to platinum-therapy.
Authors: Wungki Park, Catherine O'Connor, Joanne F. Chou, Carly Schwartz, Anna M. Varghese, Mary Larsen, Fiyinfolu Balogun, Robin Brenner, Kenneth H. Yu, Erin Diguglielmo, Shigeaki Umeda, Elias Karnoub, Fergus Keane, Haochen Zhang, Smita Suhas Joshi, Nadeem Riaz, David Paul Kelsen, Marinela Capanu, Christine A Iacobuzio-Donahue, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2023)

4140 Background: Maintenance olaparib improves PFS in g BRCA1/2m (core HRD) in mPDAC (Golan, NEJM 2019). Whether other HRD indicators, such as gene mutations other than g BRCA1/2m (non-Core HRD, Cohort B) and exceptional platinum responders (Cohort C, response &gt; 6 months) may benefit from PARPi in mPDAC remains unanswered. We hypothesized that pembrolizumab and olaparib (POLAR) combination may improve outcome by immunogenic cell death. Methods: We conducted an open-label, non-randomized, phase 2 trial of POLAR as maintenance therapy for pts with mPDAC whose disease had not progressed for 4 months (m) in Cohort B or 6 m in C. Herein, we report on Cohorts B &amp; C. Eligibility: ECOG 0-1, mPDAC meeting eligibility of B or C. POLAR (Pembrolizumab 200mg IV Q3W+ OLApaRib 300mg BID) until disease progression or limiting toxicity. Objective response rate (ORR), median PFS (mPFS), median overall survival (mOS), disease control rate (DCR), CA 19-9, cfDNA and baseline HRD mutational signature were analyzed. Results: Cohorts B and C enrolled N=15 each. N=25 pts evaluable by RECIST 1.1. Median follow-up 9.9 (1.3-22.8) and 11.3 (5.8-23) m, respectively. Efficacy details are shown. G3-5 AEs related to treatment: 5/14 (36%): 1 diarrhea (7%), 1 hyperglycemia (7%), 2 anemia (14%), 1 lipase increased (7%). Cohort B: 9/15 (60%) ATM, 3 CHEK2, 2 MUTYH, 1 BLM, 1 FANCC. Canonical gene mutations for mPDAC were less common for pts in Cohort B, especially in ATM PA group (n=9) vs C. Median genomic instability score (GIS) was computed and higher 28 (0-38) vs 9 (0-24) in Cohort B vs C, p=0.052. Median tumor mutation burden (TMB) was not different between B and C (3.3 and 4.1). Conclusions: Clinical activity of POLAR maintenance observed in select pts in B and C. Although PFS was modest (mPFS of 4m [2.1-5.4] in B + C), an intriguing survival signal (mOS at 14m [10-NR] from first POLAR dose) was seen in select patients without chemotherapy. Extensive correlative analyses underway to evaluate response and resistance (SPORE: 1P50CA257881-01A1). Cohort A (core HRD) actively accruing. Clinical trial information: NCT04666740 . [Table: see text]
Efficacy and safety of encorafenib-based regimens in colorectal cancer: A systematic review of clinical trials.
Authors: Wajeeha Aiman, Samer Jumean, Jose Garcia, Ummul Asfeen, Osama Alkhlaifat, Murad Qirem, Mohammad Nabil Rayad, Amaar Ahmad, Theodore DaCosta, Gunwant K. Guron, Hamid Salim Shaaban
Journal: Journal of Clinical Oncology (2023)

e15600 Background: BRAF gene mutation is present in 10% of the world’s 3 rd common cancer, i.e., colorectal cancer (CRC). Constitutive activation of the mitogen-activated protein kinase pathway (MAPKP) results from this mutation, abnormal activation of MAPKP, inhibiting apoptosis and enhancing proliferative activity. In this systematic review, we will assess the efficacy of encorafenib (a BRAF inhibitor) based regimens in CRC. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Embase, and Clinicaltrials.gov with mesh terms, ‘’Colorectal Neoplasms’’ and “Proto-Oncogene Proteins B-raf” from the inception of data till 01/05/2023. We screened 4572 articles and included 1 randomized clinical trial (RCT, N = 665), and 4 non-randomized trials (nRCTs, N = 175), measuring the efficacy of encorafenib (E) based regimens in BRAF V600-mutated CRC. Results: In 4 clinical trials (N = 840), 246 patients treated with a double regimen and 373 treated with a triple regimen of E. In 2 clinical trials (N = 319), triple therapy of E + C + Binimetinib showed an overall response rate (ORR) of 47.8% and 26% in the untreated metastatic CRC (mCRC) and phase III randomized trial triple regimen arm, respectively. A recent trial on triple therapy of E + C + nivolumab (N) showed an ORR of 45% with overall survival (OS) and progression-free survival (PFS) of 11.4 and 7.3 months, respectively. In 1 randomized trial (N = 665), ORR improved from 2% in the control arm to 26% and 20% in triple and double regimens, respectively, which was mainly partial response (PR) with complete response (CR) of 4-5% in both groups. The OS was 9 and 8.4 months with a hazard ratio (HR) for death vs. control of 0.52; (95% confidence interval [CI], 0.39 to 0.70; P &lt; 0.001) and 0.60; (95% CI, 0.45 to 0.79; P &lt; 0.001) in the triple and dual regimen, respectively. In 1 trial of dose escalation study, alpelisib (A) was added to E + C and the addition of this third drug showed minimal changes in the ORR from 18 to 19%, and PFS improved from 3.7 to 4.2 months. (Table 1). Conclusions: A combination of BRAF inhibitors with anti-EGFR monoclonal antibodies showed a clinically significant increase in antitumor activity in BRAF-mutated mCRC compared to standard therapy. The addition of MEK/PI3K inhibitor as a third drug to E + C also showed some improvement in ORR and PFS. Triple therapy with E + C + N was also effective and tolerated well by the microsatellite stable (MSS) BRAF mutated mCRC population. Randomized trials are needed. [Table: see text]
Cholangiocarcinoma: A nationwide trend analysis from 2016 to 2020.
Authors: Michelle Ishaya, Rafaella Litvin, Chun-Wei Pan, Muhammad Bilal Ibrahim, Mihir Shah
Journal: Journal of Clinical Oncology (2023)

e16177 Background: Cholangiocarcinomas (CCAs) are epithelial malignancies arising from the biliary ductal system, occurring with an incidence of 1/100,000 people per year in the US. Most patients present with advanced-stage disease and prognosis is very poor, with five-year mortality rates ranging from 2-24% depending on stage and subtype. This study was designed to determine the trends and adverse outcomes of CCA. Methods: This retrospective trend study analyzes data from the Nationwide Inpatient Sample (NIS) for the years 2016-2020 to identify adult hospitalizations with a diagnosis of cholangiocarcinoma and to highlight epidemiological trends. Inpatient mortality, mean length of stay (LOS), mean total hospital charge (THC), and rates of procedures and complications were estimated. Multivariate regression trend analysis was used to assess statistical significance and adjust for confounders. Results: There was an increase in the number of CCA hospitalizations per total hospitalizations from 8.49/100,000 in 2016 to 11.0/100,000 in 2020 (p &lt; 0.01). Mean age remained around 67 years old, and male predominance remained constant throughout this period (52.7%). White patients made up the majority of the study population (65.6%). Inpatient mortality ranged from 6.8% to 7.1%, with no statistically significant trend. However, there was an increase in mean THC (P-trend &lt;0.05) with no significant change in mean LOS (P-trend 0.76). We found a decrease in endoscopic retrograde cholangiopancreatographies (ERCPs) performed (1.6% to 1.2%, p=0.05), biliary duct stents placed (1.2% to 0.6%, p=0.003), and percutaneous biliary tract drains placed (4.2% to 3.4%, p=0.002) from 2016 to 2020. An increase was seen in rates of acute kidney injury (AKI) (22.9% to 28.6%, P&lt;0.05), stent-related complications (2.0% to 2.6%, P=0.01), and peritoneal metastasis (7.7% to 9.3%, P&lt;0.05). Biliary duct obstruction, stent-related infection, and palliative care utilization did not show any statistically significant change during this time. Conclusions: CCA hospitalizations increased from 2016 to 2020. Demographics remained unchanged, with a stable inpatient mortality rate but increased THC. The use of ERCPs, biliary duct stents, and percutaneous biliary tract drainage devices decreased, but rates of AKI, stent-related complications, and peritoneal metastasis increased. It is unclear what factors led to decreased procedure rates and increased complication rates. No significant changes were observed in biliary duct obstruction, stent-related infections, or palliative care utilization.[Table: see text]
Efficacy and safety of regorafenib alone or in combinations in the second-line setting for advanced hepatocellular carcinoma: A multicenter real-world study.
Authors: Wei Zhang, Yanrong Zhao, Guixiang Ma, Yu Zhang, Yuan Guo, Zhong Chen
Journal: Journal of Clinical Oncology (2023)

e16172 Background: Due to drug resistance or intolerable adverse events, most hepatocellular carcinoma (HCC) patients tend to experience TKI-based first-line therapy failure. However, there is no unified choice of second-line treatment after this. Different authors have demonstrated that the combination of regorafenib and PD-1 inhibitors or TACE depicts synergistic effect. Therefore, the major goal of this research is to explore the efficacy and safety of regorafenib alone or in combinations as second-line therapy for advanced HCC in a real-world setting. Methods: In this study 94 advanced HCC patients (84 male and 10 females, average age of 59.8 years) were included from 3 Chinese centers between September 2018 and August 2022. It includes pathologically or clinically diagnosed advanced HCC patients who received regorafenib alone or in combinations in the second-line setting for at least 28 consecutive days. The primary endpoints were objective response rate (ORR, mRECIST criteria), and progression-free survival (PFS), however, the secondary endpoints included overall survival (OS) rate at 12-month, disease control rate (DCR) and treatment-related adverse events (TRAEs). Statistical analysis was performed with Kaplan-Meier method by using log-rank test. Results: 32 (34.0%) patients had BCLC stage B (others had BCLC stage C) and 72 (76.6%) patients were of Child-Pugh A (others were of Child-Pugh B). Half of the patients received regorafenib 160mg once daily during weeks 1–3 of each 4-week cycle. The proportions of patients received single drug regorafenib therapy (REGO) and combination therapies (COM) were 26.6% and 73.4%, respectively. The combination treatment regimens included regorafenib plus PD-1 inhibitors (36.2%), regorafenib combined with TACE (11.7%), and triple therapy (regorafenib, PD-1 inhibitors, TACE) (25.5%). The ORR and DCR were 28.7% and 72.3% with a median PFS of 8.4 months (range 6.33-10.47) and 12-month OS rate was 92.6%. The median PFS of COM group was 8.7 months ranging from 7.09-10.32, which was significantly longer compared to REGO group (4.2 months, range 0.45-7.95) (P = 0.031). Moreover, 66 (70.2%) recipients had TRAEs and most frequent TEAEs (≥5%) included hand-foot syndrome (31.9%), diarrhea (20.2%), rash (13.8%), fatigue (7.4%), oral mucositis (7.4%) and arthralgia (5.3%). 12 (12.8%) recipients had grade 3 TRAEs, including hand-foot syndrome (8.5%), hypertension (2.1%), diarrhea (1.1%) and rash (1.1%). No Grade 4 TRAE and new safety signal were identified. Conclusions: In the second-line treatment of advanced HCC, regorafenib alone or in combinations is effective and well-tolerated. The combination therapy showed a longer survival than regorafenib alone.
UPGRADE-A: Phase 1 expansion trial of the NaPi2b-directed antibody drug conjugate (ADC) upifitamab rilsodotin (UpRi) in combination with carboplatin in patients with high-grade serous ovarian cancer (HGSOC).
Authors: John L. Hays, Claire Frances Friedman, Nehal Lakhani, Charles K Anderson, Joseph Buscema, Linda R. Duska, Erika P. Hamilton, Sarah E. Taylor, Cassandra Carrington, Robert Allen Burger, Theresa Louise Werner
Journal: Journal of Clinical Oncology (2023)

TPS5613 Background: UpRi is a first in class NaPi2b ADC with a novel scaffold-linker-payload that is designed to enable high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in HGSOC, with limited expression in healthy tissues. Interim data from a previous phase 1b study of heavily pretreated HGSOC patients reported clinical activity and tolerability data for UpRi as a monotherapy, most notably in patients with NaPi2b positive tumors (TPS≥75). Based on these emerging single-agent safety and efficacy data, it is hypothesized that UpRi in combination with carboplatin may provide additional clinical benefit for patients in earlier lines of treatment. UPGRADE-A is a Phase 1 dose escalation (DES) and expansion (EXP) study to evaluate UpRi and carboplatin followed by UpRi maintenance in recurrent platinum-sensitive HGSOC. The DES portion of UPGRADE-A has completed enrollment, and the EXP portion is ongoing. Methods: The EXP cohort of UPGRADE-A is enrolling patients with recurrent or metastatic PSOC (defined as having achieved a PR or CR to 4+ cycles in their last platinum containing regimen) who have received 1-3 prior lines of therapy. Up to 1 non-platinum based prior chemotherapy regimen is allowed, provided it is not the most recent line of chemotherapy. The primary objective of EXP is feasibility of UpRi + carboplatin at the RP2D, defined as 60% of patients completing at least 4 cycles of UpRi + carboplatin without discontinuing treatment early for reasons other than disease progression. Secondary objectives include the safety/tolerability, pharmacokinetics, and preliminary anti-neoplastic activity of the UpRi + carboplatin combination. Tumor tissue must be provided (archival or fresh sample) for retrospective NaPi2b assessment. UpRi 30mg/m2 + carboplatin (AUC 5) will be administered IV every 28 days for up to 6 cycles, followed by UpRi maintenance monotherapy until disease progression or unacceptable toxicity. Up to 30 patients are expected to enroll in EXP, and the trial is currently open for enrollment. NCT04907968. Clinical trial information: NCT04907968 .